Medicine

Class 12 Chemistry, unit 21, book pages 323–331

Practise 31 MCQs Take the unit quiz Review 47 cards

Medicinal chemistry explains how a drug acts on the body at the level of molecules. This unit covers the safe dose range of a drug (the therapeutic window), how aspirin, penicillin and opiates work, and how their structures explain their action. It also explains why the stomach is kept strongly acidic, what non-specific reactions and active metabolites are, and why viral infections are harder to treat than bacterial ones.

Learning outcomes (5)

Recognise the concept of therapeutic index and therapeutic window in relation to drug administration.
Explain the mechanism of action and uses of aspirin and penicillin, and explain the chemical structure of each.
Describe the mechanism of action of opiates and the concept of opioid receptors in the brain.
Describe the pH regulation of the stomach and its relation to the concept of non-specific reactions and active metabolites.
Recognise the challenges in treating viral infections with drugs and the concept of antiviral medications.

21.1Therapeutic index and therapeutic windowOften examined

A medicine works only in the right amount. Too little drug in the blood gives no benefit, and too much causes harmful (toxic) effects. The therapeutic window, also called the therapeutic range or, in this book, the therapeutic index, is the range of drug amounts (concentrations) in the body that bring about the desired therapeutic effect with minimum adverse effects. It is the dosage range in which a medicine is both effective and safe.

Key components of the therapeutic window (21.1.1)

Minimum effective concentration (MEC): The lowest concentration of a drug in the bloodstream that triggers the desired therapeutic effect. Below the MEC the drug may not be effective.
Maximum tolerated concentration (MTC): The highest concentration of a drug in the bloodstream that a patient can bear without severe side effects or toxicity. Above the MTC the drug becomes toxic.
Therapeutic window: The range of concentration between the MEC and the MTC, in which the drug is both effective and safe.

MEC \leq C_{blood} \leq MTC

$C_{blood}$ is the concentration of the drug in the blood plasma, usually in $mg L^{- 1}$ . The dose and the time between doses are chosen to keep $C_{blood}$ inside this range.

The therapeutic window acts as a safety zone for drug administration. It makes sure the drug is potent enough to be effective while staying within safe limits. Falling below the MEC gives inadequate treatment, while going above the MTC leads to toxicity.

Drug level in the blood after one dose

t / h

C_{blood}

MTC

MEC

therapeutic window

toxic

ineffective

peak

normal dose

double dose

With the normal dose the level rises above the MEC after about

0.2 h

, peaks inside the window and falls below the MEC after about

5.4 h

, so the next dose is due then. A double dose rises above the MTC (from about

0.4

3.4 h

) and is toxic.

T I = \frac{T D _{50}}{E D _{50}}

Therapeutic index (ratio)

Reading the therapeutic window

A drug has MEC

= 10 mg L^{- 1}

and MTC

= 40 mg L^{- 1}

. Classify blood levels of (a)

5 mg L^{- 1}

, (b)

25 mg L^{- 1}

and (c)

50 mg L^{- 1}

. State the width of the window.

Compare each level with the two limits.
$5 < 10 (below MEC), 10 < 25 < 40 (inside), 50 > 40 (above MTC)$
Interpret: (a) too little drug, ineffective; (b) in the therapeutic window, effective and safe; (c) above the MTC, toxic.
The width of the window is the difference between the limits.
$MTC - MEC = 40 - 10 = 30 mg L^{- 1}$

(a) ineffective, (b) therapeutic, (c) toxic; window = 10 to 40 mg L^{- 1}

Factors influencing the therapeutic window (21.1.2)

Individual variability: people metabolise drugs differently because of genetic factors, age and overall health. A slow metaboliser keeps the drug longer, so a normal dose can rise above the MTC.
Drug interactions: taking several medicines at the same time can change the concentration of each drug, for example when one drug slows down the breakdown of another.
Patient characteristics: age, body weight and existing diseases (such as liver or kidney disease) affect how a drug is absorbed, distributed, metabolised and eliminated.

21.2Mechanism of drug action

Drug action is the biochemical or physiological effect that a drug produces in the body to give a therapeutic response. A drug's mechanism of action is the molecular or cellular process by which it produces this effect. Most drugs work by fitting into a target molecule in the body, like a key in a lock. The target is usually an enzyme, a receptor on a cell, or a structure that only the microorganism has.

The drugs of this unit and their targets
Drug	Target	What the drug does	Result
Aspirin	Cyclooxygenase (COX) enzyme	Blocks the enzyme permanently	Less prostaglandin and thromboxane: less pain, fever, inflammation and clotting
Penicillin	Transpeptidase enzyme of bacteria	Blocks the enzyme that cross-links the cell wall	Weak cell wall, the bacterium bursts
Opiates	Opioid receptors on nerve cells	Activate the receptors (mimic endorphins)	Pain signals blocked; euphoria
Antiviral drugs	Viral enzymes (protease, reverse transcriptase, polymerase)	Inhibit the enzyme	The virus cannot multiply

21.2.1AspirinOften examined

Mechanism of action

The primary action of aspirin is the inhibition of the enzyme cyclooxygenase (COX). This enzyme converts arachidonic acid, a fatty acid released from cell membranes, into prostaglandins and thromboxanes. Prostaglandins cause inflammation, pain and fever. Thromboxanes make blood platelets stick together (platelet aggregation), which is essential for blood clotting.

arachidonic acid COX prostaglandins (pain, fever, inflammation) + thromboxanes (clotting)

Aspirin transfers its acetyl group ( $CH X_{3} CO X^{-}$ ) to a serine $- OH$ group in the active site of COX. The acetylated enzyme can no longer bind arachidonic acid, so it stays blocked permanently (irreversible inhibition). With less prostaglandin, pain, fever and inflammation fall. With less thromboxane, platelets clump less and blood clots form less easily.

Uses

Pain relief (analgesic): headaches, muscle pain and mild arthritis.
Anti-inflammatory: reduces inflammation (swelling, redness and heat).
Antipyretic: reduces fever.
Anticoagulant (antiplatelet) effect: in low doses it prevents heart attacks and strokes by inhibiting blood clot formation.

Chemical structure

The chemical name of aspirin is acetylsalicylic acid (IUPAC name 2-ethanoyloxybenzoic acid), molecular formula $C X_{9} H X_{8} O X_{4}$ , molar mass $180 g mo l^{- 1}$ . It has three parts: a benzene ring (aromatic ring), a carboxylic acid group ( $- COOH$ ), and an ester group, the acetoxy group $- OCOCH X_{3}$ , on the next ring carbon (ortho position).

aspirin (acetylsalicylic acid) benzene ring,

- COOH

and ester

- OCOCH X_{3}

salicylic acid phenol

- OH

instead of the ester group

Preparation and hydrolysis

Aspirin is made by esterifying (acetylating) the phenolic $- OH$ group of salicylic acid with ethanoic anhydride. A few drops of concentrated sulphuric or phosphoric acid act as catalyst.

HOC X_{6} H X_{4} COOH + (CH X_{3} CO) X_{2} O H X^{+} warm CH X_{3} COOC X_{6} H X_{4} COOH + CH X_{3} COOH

salicylic acid + ethanoic anhydride $\to$ aspirin + ethanoic acid

In moist air, and in the body, the ester group is slowly hydrolysed back to salicylic acid. Old aspirin tablets smell of vinegar for this reason. Salicylic acid formed in the body also relieves pain and inflammation, so it is an active metabolite (section 21.4).

CH X_{3} COOC X_{6} H X_{4} COOH + H X_{2} O HOC X_{6} H X_{4} COOH + CH X_{3} COOH

21.2.2PenicillinOften examined

Penicillin was the first antibiotic. Alexander Fleming discovered it in 1928 in the mould Penicillium. An antibiotic is a substance that kills bacteria or stops their growth.

Mechanism of action

Bacteria are surrounded by a strong cell wall made of peptidoglycan: long sugar chains held together by short peptide cross-links. The cross-links are made by the enzyme transpeptidase (one of the penicillin-binding proteins). The wall lets the bacterium resist the high osmotic pressure of its cytoplasm.

How penicillin kills a growing bacterium

Penicillin has a shape similar to the end of the peptide chain (D-alanyl-D-alanine) that transpeptidase normally joins, so it enters the active site of the enzyme.
The strained ** $β$ -lactam ring** of penicillin opens and forms a covalent bond with a serine group in the active site. The enzyme is now permanently blocked.
The blocked enzyme cannot cross-link new peptidoglycan, so a growing bacterium builds a weak cell wall.
Water enters the cell by osmosis. The weak wall cannot resist the osmotic pressure, so the cell swells and bursts (lysis) and the bacterium dies.

Penicillin works best against Gram-positive bacteria (such as Streptococcus and Staphylococcus), whose thick peptidoglycan wall is exposed on the outside. Gram-negative bacteria have an extra outer membrane that keeps many penicillins out.

Uses

Pneumonia and other respiratory tract infections.
Meningitis.
Skin infections.
Syphilis.
Throat infections (such as strep throat).

Chemical structure

The key structural feature of all penicillins is the **four-membered $β$ -lactam ring, a cyclic amide. This ring is essential for antibacterial activity. It is fused to a five-membered thiazolidine ring**, which contains a sulphur atom and a nitrogen atom. The molecule also has a carboxylic acid group ( $- COOH$ ), two methyl groups and an amide side chain $R - CO - NH X^{-}$ . Different penicillins differ only in the group R.

penicillin G (benzylpenicillin) R = benzyl,

C X_{6} H X_{5} CH X_{2} X^{-}

amoxicillin same core, different R group; acid-stable, taken by mouth

Functional groups of penicillin
Part of the molecule	Why it matters
$β$ -lactam ring (4-membered cyclic amide)	Its bond angles are about $9 0^{\circ}$ instead of $109. 5^{\circ}$ or $12 0^{\circ}$ , so the ring is strained. It opens easily and bonds to transpeptidase. If this ring is broken, penicillin is inactive.
Thiazolidine ring (5-membered, contains S and N)	Holds the $β$ -lactam ring in a bent, strained shape and gives the molecule the right shape to fit the enzyme.
Carboxylic acid group ( $- COOH$ )	Binds to the active site by ionic attraction; forms water-soluble sodium or potassium salts for injection.
Side chain $R - CO - NH X^{-}$	Controls acid stability (whether it can be taken by mouth), the range of bacteria killed, and resistance to $β$ -lactamase.

Resistance to penicillin

** $β$ -lactamase (penicillinase) enzymes** made by some bacteria hydrolyse (open) the $β$ -lactam ring before the drug reaches its target.
Altered target enzymes: changed penicillin-binding proteins bind penicillin weakly, as in MRSA (methicillin-resistant Staphylococcus aureus).
Reduced entry or pumping out: fewer pores in the outer membrane, or efflux pumps that push the drug out.

Resistance is overcome by giving a $β$ -lactamase inhibitor such as clavulanic acid together with amoxicillin (co-amoxiclav), by using $β$ -lactamase-resistant penicillins such as flucloxacillin, by switching to another antibiotic such as vancomycin for MRSA, and by using antibiotics only when needed and completing the full course.

21.2.3Opiates

Opiates, also called opioids, are a class of drugs with strong pain-relieving (analgesic) effects. They include the illegal drug heroin, synthetic opioids such as fentanyl, and legal prescription painkillers such as oxycodone, hydrocodone, codeine and morphine. They produce euphoria (an intense feeling of well-being) and, unfortunately, addiction. Their action involves binding to opioid receptors in the brain and throughout the central nervous system.

morphine natural opiate: phenol

- OH

, tertiary amine N

codeine phenol

- OH

of morphine changed to

- OCH X_{3}

Heroin is made by acetylating both $- OH$ groups of morphine. Fentanyl is fully synthetic and has a different skeleton, but it still has a basic nitrogen and a benzene ring that fit the same receptor.

heroin (diacetylmorphine) both

- OH

groups changed to ester groups

fentanyl fully synthetic, 50 to 100 times stronger than morphine

Oxycodone and hydrocodone are semi-synthetic prescription painkillers made from opium alkaloids; compare them with codeine.

oxycodone semi-synthetic: ketone group and extra

- OH

hydrocodone semi-synthetic: ketone group, no

- OH

Drug	Type	Notes
Morphine	natural (opium)	the standard strong painkiller for severe pain
Codeine	natural (opium)	methyl ether of morphine's phenol $- OH$ ; weaker; used for mild pain and cough; the liver converts part of it into morphine
Heroin	semi-synthetic, illegal	both $- OH$ groups of morphine changed to ester groups; more fat-soluble, so it enters the brain very fast; highly addictive
Oxycodone, hydrocodone	semi-synthetic	prescription painkillers
Fentanyl	fully synthetic	about 50 to 100 times stronger than morphine; a tiny overdose can kill

21.2.4Opioid receptors and the mechanism of opiatesOften examined

Opioid receptors are protein molecules on the surface of nerve cells in the brain, spinal cord and gut. They are part of the body's natural pain-relief system and are normally activated by endorphins, small peptides that the body releases during pain, stress or exercise. There are three main types.

The three main opioid receptors
Receptor	Main role	Effects of activation
Mu ( $μ$ )	Mainly responsible for the analgesic effects of opiates; the main target of most clinically used opioids	Strong pain relief, euphoria, respiratory depression (slow breathing), physical dependence; also sedation and constipation
Delta ( $δ$ )	Function not fully understood	Thought to add to pain relief and to play a role in mood regulation
Kappa ( $κ$ )	Pain relief, especially in the spinal cord	Pain relief, but in some cases dysphoria (unpleasant mood) and hallucinations

Mechanism of action

How opiates relieve pain

Opiates have a shape similar to endorphins, so they bind to opioid receptors on cells in the brain, spinal cord and other body areas.
They activate these receptors as endorphins do (they are agonists), but more strongly and for longer. This switches on the body's own pain-relief system.
In the pain pathway the activated receptor closes $Ca X^{2 +}$ channels in the nerve ending, so less pain neurotransmitter (such as substance P) is released. It also opens $K X^{+}$ channels in the next nerve cell, so that cell fires less.
Fewer pain signals reach the brain, and the brain's perception of pain is dulled. The result is powerful analgesia (pain relief).
In the brain's reward centre, opiates cause nerve cells to release much more dopamine. This produces euphoria and well-being. Alcohol, nicotine, amphetamines and cocaine trigger the same dopamine surge, which is why all of them can be addictive.

One receptor, two outcomes: pain relief (the medical use) and euphoria (the cause of abuse and addiction).

Therapeutic uses of opioids

Pain management: moderate to severe pain (after surgery, injury or in cancer), especially when other pain relievers are ineffective.
Cough suppression: some opiates, such as codeine, are antitussive (cough suppressants).
Diarrhoea treatment: opioids decrease bowel motility (movement), relieving diarrhoea; loperamide is an example.

Risks and considerations

Abuse: Using a drug for its euphoric effect rather than for a medical need.
Tolerance: The need for a higher dose to get the same effect after long-term use.
Physical dependence: The body adapts to the drug and needs it to function normally.
Addiction: Compulsive use of a drug despite harm, driven by craving.
Withdrawal symptoms: Unpleasant effects (pain, sweating, diarrhoea, anxiety, sleeplessness) when the drug is stopped abruptly.
Overdose: Too much opioid depresses breathing and can cause death, especially with potent synthetic opioids like fentanyl.

The antidote for an opioid overdose, naloxone, is an antagonist. It binds more strongly to $μ$ receptors, pushes the opioid off and reverses the overdose within minutes.

Long-term effects on brain chemistry

Fewer working receptors: $μ$ receptors become desensitised, and many are taken into the cell (down-regulation), so the receptor density on the cell surface falls. A larger dose is then needed for the same effect (tolerance).
Less natural endorphin: the body makes fewer endorphins because the drug is doing their job.
Reset reward system: normal pleasures (food, company) now release too little dopamine to feel rewarding, while the drug becomes the main source of reward. This drives craving.
Rebound over-activity: nerve cells that were slowed by the drug become over-active when it is removed (for example a surge of noradrenaline), giving withdrawal symptoms.

21.3pH regulation in the stomachOften examined

The stomach keeps its contents strongly acidic. This regulation is a dynamic, tightly controlled process needed for proper digestion and enzyme activation. Parietal cells in the gastric glands of the stomach lining release hydrochloric acid ( $HCl$ ) into the stomach lumen (the space inside the stomach). The acid breaks down ingested food, activates digestive enzymes, denatures proteins and kills harmful microorganisms in food.

How parietal cells make the acid

Carbon dioxide and water combine inside the parietal cell. The enzyme carbonic anhydrase speeds this up.
$CO X_{2} + H X_{2} O carbonic anhydrase H X_{2} CO X_{3} H X^{+} + HCO X_{3} X^{-}$
A proton pump ( $H X^{+}$ / $K X^{+}$ -ATPase) uses energy from ATP to pump $H X^{+}$ ions into the lumen in exchange for $K X^{+}$ ions.
Chloride ions ( $Cl X^{-}$ ) follow into the lumen, so the stomach contents are effectively dilute hydrochloric acid. The $HCO X_{3} X^{-}$ ions pass into the blood.

pH level in the stomach

The stomach's pH typically ranges from 1.5 to 3.5. This acidic environment is needed for the best enzyme function, especially of pepsin, which breaks proteins down into smaller peptides.

Hydrogen ion concentration in the stomach

Find

[H X^{+}]

at pH 1.5 and at pH 3.5. How many times more acidic is pH 1.5?

Rearrange $pH = - lo g [H X^{+}]$ to get the concentration.
$[H X^{+}] = 1 0^{- pH}$
Substitute each pH value.
$[H X^{+}]_{1.5} = 1 0^{- 1.5} = 3.2 \times 1 0^{- 2} mol d m^{- 3}, [H X^{+}]_{3.5} = 1 0^{- 3.5} = 3.2 \times 1 0^{- 4} mol d m^{- 3}$
Divide. A difference of 2 pH units is a factor of $1 0^{2}$ .
$\frac{3.2 \times 1 0 ^{- 2}}{3.2 \times 1 0 ^{- 4}} = 100$

[H X^{+}] falls from 3.2 \times 1 0^{- 2} to 3.2 \times 1 0^{- 4} mol d m^{- 3} : pH 1.5 is 100 times more acidic

Functions of stomach acid

Activates digestive enzymes: acid converts the inactive enzyme pepsinogen into active pepsin and keeps the pH at pepsin's optimum (about 2).
Denatures proteins: acid unfolds food proteins so pepsin can reach their peptide bonds.
Kills microorganisms in food and water, protecting against infection.
Helps the absorption of iron and vitamin $B_{12}$ .

pepsinogen (inactive) H X^{+} pepsin (active) + small peptide

Control mechanisms

The release of $HCl$ is regulated by (1) the presence of food in the stomach, (2) hormonal signals, mainly the hormone gastrin, and (3) neural signals from the brain through the vagus nerve. When the pH falls too low, gastrin release is switched off (negative feedback), so the acidity stays in range.

Mg (OH) X_{2} + 2 HCl Al (OH) X_{3} + 3 HCl MgCl X_{2} + 2 H X_{2} O AlCl X_{3} + 3 H X_{2} O

21.4Non-specific reactions and active metabolites

Non-specific reactions

Enzyme reactions are specific: each enzyme acts on one substrate or one type of bond, like a key that fits one lock. Non-specific reactions are reactions that occur without specificity to a particular substrate; they act on many different substances in the same way.

Stomach acid is the best example. The low pH of the stomach lumen kills pathogens in food and helps break down complex food molecules such as proteins, lipids and carbohydrates. The stomach's \ce{HCl} unfolds (denatures) every protein, whatever it is, making it more accessible for enzymatic digestion by pepsin.

Feature	Specific (enzyme) reaction	Non-specific reaction
Substrate	one substrate or one type of bond	many different substances
Agent	an enzyme with a shaped active site	a general condition such as low pH
Example	pepsin hydrolyses peptide bonds	\ce{HCl} denatures all proteins and kills most microbes

Active metabolites

A metabolite is a substance formed when the body's metabolic processes change a drug. An active metabolite is a metabolite that is itself biologically active. The book describes a metabolite as a biologically active form of a drug produced by the body's metabolic processes. A drug given in an inactive form that the body converts into the active form is called a prodrug.

The stomach's pH can affect the formation of metabolically active drugs. Some medicines change significantly in the stomach because of the acidic environment and enzyme activity. The products may be the active form of the drug, or the change may make the drug inactive.

Examples of active and inactive metabolites
Drug	What happens	Result
Omeprazole (ulcer drug)	acid converts it into its active form inside the acid spaces of parietal cells	active metabolite formed, which blocks the proton pump
Penicillin G	stomach acid opens its \beta-lactam ring	inactive, so penicillin G is injected; acid-stable amoxicillin is taken by mouth
Aspirin	ester group hydrolysed	salicylic acid, an active metabolite
Codeine	converted into morphine in the liver	most of its pain relief comes from the morphine formed

21.5Viral infections and their treatmentOften examined

Unlike bacteria, viruses lack many cellular structures and metabolic pathways. A virus is only genetic material (DNA or RNA) inside a protein coat. It multiplies inside a host cell using the host's own machinery, so it is difficult to attack the virus without also harming the host cell. Treating viral infections with medicines therefore presents unique challenges.

Why antibiotics cannot treat viral infections
Feature	Bacteria	Viruses
Size	about 1 to 5\,\mu\mathrm{m} (light microscope)	about 20 to 300\,\mathrm{nm} (electron microscope)
Structure	complete cell: cell wall, membrane, ribosomes, cytoplasm	genetic material in a protein coat; no cell wall, no ribosomes
Reproduction	divide on their own	only inside a host cell
Metabolism	own enzymes and pathways	none of their own; use the host's
Treated by	antibiotics	antiviral drugs (antibiotics do not work)

How antiviral drugs work

Antiviral drugs are developed to disrupt the viral life cycle at different stages of replication: by preventing the virus from entering host cells, by inhibiting the replication of the viral genome, or by stopping the release of new virus particles.

Stages of the viral life cycle (black) and the antiviral drugs that block them (accent). RT = reverse transcriptase.

Enzyme inhibition is the most common mechanism, because viral enzymes are essential for replication and many are not found in human cells. Protease inhibitors, reverse transcriptase inhibitors and polymerase inhibitors break the viral life cycle. Viral protease inhibitors target the viral proteases that cut long viral proteins into working pieces; they are frequently used for HIV and hepatitis C infections.

Stage blocked	Drug class	Example (virus)
Entry into the host cell	entry (fusion) inhibitors	enfuvirtide (HIV)
Copying the genome	reverse transcriptase inhibitors	zidovudine, tenofovir (HIV)
Copying the genome	polymerase inhibitors	acyclovir (herpes), sofosbuvir (hepatitis C)
Processing viral proteins	protease inhibitors	ritonavir (HIV), glecaprevir (hepatitis C)
Release of new viruses	neuraminidase inhibitors	oseltamivir (influenza)
Host defence	immune boosters	interferons (hepatitis B and C)

acyclovir guanine base with an open chain in place of a sugar

zidovudine (AZT) thymidine analogue with \ce{-N3} in place of the 3'-OH

Both drugs look like normal DNA building blocks (nucleosides), so the viral polymerase or reverse transcriptase puts them into the growing DNA chain. They lack the \ce{-OH} group needed to attach the next unit, so the chain stops growing.

Besides enzyme inhibition, some antiviral drugs enhance the host's immune response. Interferons are proteins that boost the immune system's ability to fight viruses.

To combat drug resistance and viral diversity, combination therapy is commonly used: several antiviral drugs with different mechanisms are given together. A virus would need several mutations at the same time to escape all of them, so the risk of resistance falls and treatment works better. HIV is treated in this way.

Challenges in treating viral infections (21.5.1)

Viruses and bacteria have different structures. Viruses can develop a protective covering around themselves, and unlike bacteria they do not have cell walls that antibiotics can attack. So the treatment of viral infections poses many challenges:

Viruses multiply inside host cells using the host's ribosomes, so treating the infection without harming the host cell needs very specific antiviral agents.
Rapid mutation: viruses mutate quickly and produce new strains. This fast mutation rate causes resistance to antiviral medicines and complicates ongoing treatment.
Few targets: viruses lack a cell wall and metabolic pathways, the usual targets of antibacterial drugs, so antiviral drugs have fewer targets.
Dormancy: some viruses develop a protective covering and can remain dormant in the body for a long time (for example herpes viruses and HIV), where drugs cannot reach them.
Toxicity: antiviral medicines may affect host cell functions and cause toxic side effects. The selectivity of the drug must be balanced to minimise harm to the host.

21.6Concept of antiviral drugs

Antiviral drugs are a class of medicines used specifically to treat viral infections. Viruses are among the major pathogenic (disease-causing) agents and cause serious diseases in humans, animals and plants. Antiviral medicines disrupt the viral life cycle by inhibiting specific stages of replication, such as blocking virus entry into host cells.

Most antiviral drugs are virustatic: they stop the virus from multiplying, and the immune system then clears the infection.
Most antivirals act on one virus or a narrow group of viruses (oseltamivir acts only on influenza). Broad-spectrum antivirals are rare because viruses differ so much.
Antibiotics are useless against viruses, because viruses have no cell wall, ribosomes or metabolism of their own to attack.
Vaccines prevent viral infection by training the immune system in advance, while antiviral drugs treat an infection that has already started.

Formula sheet

Therapeutic window

\text{MEC}\le C_{\text{blood}}\le\text{MTC}

C_{\text{blood}}: drug concentration in the blood; MEC: minimum effective concentration; MTC: maximum tolerated concentration

\mathrm{mg\,L^{-1}} (any concentration unit)

Therapeutic index (ratio form)

TI=\dfrac{TD_{50}}{ED_{50}}

TD_{50}: dose toxic in 50% of patients; ED_{50}: dose effective in 50% of patients; a larger TI means a safer drug

no unit (a ratio)

pH of stomach contents

\mathrm{pH}=-\log_{10}[\ce{H+}]

[\ce{H+}]: hydrogen ion concentration; stomach pH is 1.5 to 3.5

Unit: [\ce{H+}] in \mathrm{mol\,dm^{-3}}

Synthesis of aspirin

\ce{HOC6H4COOH + (CH3CO)2O ->[H+] CH3COOC6H4COOH + CH3COOH}

salicylic acid + ethanoic anhydride gives aspirin + ethanoic acid (acid catalyst, warm); aspirin keeps the benzene ring and \ce{-COOH} and gains an acetoxy ester group

Hydrolysis of aspirin

\ce{CH3COOC6H4COOH + H2O -> HOC6H4COOH + CH3COOH}

aspirin + water gives salicylic acid (active metabolite) + ethanoic acid; the acetoxy ester group is split off

Acid formation in parietal cells

\ce{CO2 + H2O <=> H2CO3 <=> H+ + HCO3-}

catalysed by carbonic anhydrase; the \ce{H+} is pumped into the stomach

Antacid neutralisation

\ce{Mg(OH)2 + 2HCl -> MgCl2 + 2H2O}

a base neutralises excess stomach acid

Key terms

Therapeutic window: The range of drug concentration in the body, between the MEC and the MTC, that gives the desired effect with minimum adverse effects. Also called therapeutic range or (in the book) therapeutic index.
Therapeutic index (ratio): In pharmacology, TD_{50}/ED_{50}; a large value means a wide safety margin.
Minimum effective concentration (MEC): The lowest blood concentration of a drug that triggers the desired therapeutic effect.
Maximum tolerated concentration (MTC): The highest blood concentration of a drug that a patient can bear without severe side effects or toxicity.
Drug action: The biochemical or physiological effect that a drug produces in the body to give a therapeutic response.
Mechanism of action: The molecular or cellular process by which a drug produces its effect.
Cyclooxygenase (COX): The enzyme that converts arachidonic acid into prostaglandins and thromboxanes; aspirin inhibits it.
Prostaglandins: Substances made by COX that cause inflammation, pain and fever.
Thromboxanes: Substances made by COX that cause platelet aggregation and blood clotting.
Analgesic: A painkiller.
Antipyretic: A drug that reduces fever.
Anti-inflammatory: A drug that reduces inflammation (swelling, redness and heat).
Acetylsalicylic acid: The chemical name of aspirin, \ce{C9H8O4}: a benzene ring with a \ce{-COOH} group and an ester (\ce{-OCOCH3}) group.
Antibiotic: A substance that kills bacteria or stops their growth, such as penicillin.
\beta-lactam ring: The strained four-membered cyclic amide ring of penicillin that is essential for its antibacterial activity.
Thiazolidine ring: The five-membered ring containing S and N that is fused to the \beta-lactam ring in penicillin.
Transpeptidase: The bacterial enzyme that cross-links peptidoglycan in the cell wall; penicillin blocks it.
Peptidoglycan: The polymer of sugar chains cross-linked by peptides that makes the bacterial cell wall.
\beta-lactamase: A bacterial enzyme that opens the \beta-lactam ring and makes penicillin inactive (a cause of resistance).
Opiates (opioids): Drugs such as morphine, codeine, heroin and fentanyl that relieve pain by acting on opioid receptors.
Opioid receptors: Receptor proteins (\mu, \delta, \kappa) on nerve cells that are activated by endorphins and by opiates.
Endorphins: The body's own pain-relieving peptides that activate opioid receptors.
Euphoria: An intense feeling of well-being; produced by opiates through dopamine release.
Dysphoria: An unpleasant, uneasy mood; a possible effect of kappa receptor activation.
Tolerance: The need for higher doses of a drug to produce the same effect.
Physical dependence: A state in which the body needs a drug to function normally, so stopping it causes withdrawal symptoms.
Addiction: Compulsive drug use despite harm, driven by craving.
Antitussive: A cough suppressant, such as codeine.
Parietal cells: Cells in the gastric glands of the stomach that secrete hydrochloric acid.
Pepsin: The stomach enzyme that digests proteins; it is formed from pepsinogen by acid and works best at about pH 2.
Gastrin: A hormone that stimulates the release of acid in the stomach.
Non-specific reaction: A reaction that occurs without specificity to a particular substrate, such as the denaturing of all proteins by stomach acid.
Metabolite: A substance formed when the body's metabolism changes a drug.
Active metabolite: A metabolite that is itself biologically active, such as salicylic acid from aspirin.
Prodrug: An inactive drug that the body converts into its active form.
Antiviral drug: A medicine used specifically to treat viral infections by disrupting the viral life cycle.
Protease inhibitor: An antiviral drug that blocks the viral enzyme that cuts viral proteins into working pieces (used for HIV and hepatitis C).
Reverse transcriptase inhibitor: An antiviral drug that stops HIV copying its RNA into DNA.
Interferons: Proteins that boost the immune system's ability to fight viruses.
Combination therapy: Treatment with several drugs that act by different mechanisms, to reduce resistance and improve results.

Multiple choice questionsp. 327–328

i1 mark

What is the significance of maintaining an acidic pH in the stomach for digestion?

AEnhances the absorption of lipids
BFacilitates the activation of digestive enzymesAnswer
CPromotes the breakdown of carbohydrates
DIncreases the secretion of bile

Why

Stomach acid converts inactive pepsinogen into active pepsin and keeps the pH near pepsin's optimum. Lipid absorption and bile action happen in the small intestine, and starch digestion by amylase actually stops in the acidic stomach.

ii1 mark

Which opioid receptor is primarily responsible for the analgesic effects of opiates?

ADelta (\delta) receptors
BKappa (\kappa) receptors
CMu (\mu) receptorsAnswer
DSigma (\sigma) receptors

Why

Mu receptors are mainly responsible for the analgesic effects of opiates and are the main targets of most clinically used opioids such as morphine. Sigma receptors are not counted among the three main opioid receptors.

iii1 mark

What is a major challenge in developing broad-spectrum antiviral drugs?

AHigh mutation rate of virusesAnswer
BLack of selectivity
CLimited understanding of viral replication
DInability to target host cells

Why

Viruses mutate rapidly and produce new strains with changed enzymes, and different viruses use different enzymes, so a drug that works on one soon meets resistance or fails on another. The book names this rapid mutation as a main challenge.

Lack of selectivity (B) is a general problem of antivirals rather than of broad-spectrum design, and D is not a goal: a drug should avoid harming host cells.

iv1 mark

Why is understanding the mechanism of action of a drug essential for healthcare professionals?

ATo identify potential side effects
BTo determine the optimal dosage
CTo assess drug interactions
DAll of the aboveAnswer

Why

Knowing how and where a drug acts lets a doctor predict its side effects, choose a dose that keeps it inside the therapeutic window, and foresee interactions with other medicines. All three reasons are correct.

v1 mark

Which of the following best describes the therapeutic window?

AThe range of drug concentrations that is toxic
BThe range of drug concentrations that produces therapeutic effects without causing significant adverse effectsAnswer
CThe range of drug concentrations that is ineffective
DThe range of drug concentrations that causes adverse effects

Why

The therapeutic window lies between the MEC and the MTC: the drug is effective and safe. Option A describes concentrations above the MTC and option C those below the MEC.

vi1 mark

If a drug's concentration in the bloodstream falls below the MEC, what is the most likely outcome?

AThe patient will experience toxicity
BThe drug will have no therapeutic effectAnswer
CThe patient will experience severe side effects
DThe drug will be at its maximum effectiveness

Why

The MEC is the lowest concentration that triggers the desired effect, so below it the drug does not work. Toxicity and severe side effects occur above the MTC, not below the MEC.

vii1 mark

What is the primary therapeutic use of aspirin?

AAntibacterial
BAnalgesic and anti-inflammatoryAnswer
CAntiviral
DAntifungal

Why

Aspirin inhibits cyclooxygenase, lowering prostaglandins, so it relieves pain (analgesic) and inflammation (it also lowers fever). It has no action against bacteria, viruses or fungi.

viii1 mark

Penicillin is most effective against which type of organisms?

AViruses
BFungi
CGram-positive bacteriaAnswer
DProtozoa

Why

Penicillin blocks the building of the peptidoglycan cell wall. Gram-positive bacteria have a thick, exposed peptidoglycan wall, so they are most sensitive. Viruses, fungi and protozoa have no peptidoglycan wall.

ix1 mark

How does penicillin inhibit bacterial growth?

ABy disrupting bacterial DNA synthesis
BBy inhibiting the enzyme responsible for cell wall synthesisAnswer
CBy disrupting bacterial protein synthesis
DBy inhibiting bacterial RNA synthesis

Why

The \beta-lactam ring of penicillin bonds to transpeptidase, the enzyme that cross-links the cell wall. The weak wall bursts under osmotic pressure. DNA, RNA and protein synthesis are targets of other antibiotics.

x1 mark

Which of the following is a common therapeutic use of opiates?

ATreating bacterial infections
BReducing inflammation
CRelieving severe painAnswer
DLowering blood pressure

Why

Opiates are strong analgesics used for moderate to severe pain, and also for cough and diarrhoea. They do not treat infections, inflammation or high blood pressure.

xi1 mark

Why can long-term use of opiates lead to addiction?

ABecause they inhibit serotonin reuptake
BBecause they cause irreversible binding to receptors
CBecause they increase dopamine release in the brainAnswer
DBecause they decrease the production of natural endorphins

Why

Opiates boost dopamine release by neurons in the brain's reward centre, giving euphoria that the user wants to repeat; this is the book's explanation of addiction.

Opioid binding is reversible (naloxone can displace it), and serotonin reuptake inhibition is how some antidepressants act. Reduced endorphin production (D) does happen with long use, but it explains dependence and withdrawal rather than the reward that drives addiction.

Short answer questionsp. 328

i3 marks

Explain the role of hydrochloric acid in the stomach and its impact on the activation of digestive enzymes.

Solution

Parietal cells in the gastric glands secrete hydrochloric acid into the stomach and keep the pH at about 1.5 to 3.5. The acid has three roles. (1) It activates enzymes: it converts the inactive enzyme pepsinogen into active pepsin and then keeps the pH at pepsin's optimum (about 2), so proteins are broken into peptides. (2) It denatures (unfolds) proteins, exposing their peptide bonds to pepsin. (3) It kills microorganisms in food.

\text{pepsinogen (inactive)}\xrightarrow{\ \ce{HCl}\ }\text{pepsin (active)}

Without enough acid, pepsinogen stays inactive and protein digestion is poor.

ii3 marks

Briefly describe how opioids activate mu receptors and how this activation leads to pain relief.

Solution

Opioids such as morphine have a shape similar to the body's own endorphins. They fit into **\mu (mu) opioid receptors on nerve cells in the brain and spinal cord and activate** them, acting as agonists. The activated receptor switches on signals inside the nerve cell: calcium channels in the nerve ending close, so less pain neurotransmitter (such as substance P) is released, and potassium channels open, so the next nerve cell becomes harder to fire.

As a result fewer pain signals reach the brain, and the brain's perception of pain is also dulled. This gives strong pain relief (analgesia).

iii3 marks

Discuss two challenges in developing antiviral drugs and provide potential strategies to overcome them.

Solution

Viruses multiply inside host cells. A virus uses the host cell's ribosomes and enzymes, so a drug that stops the virus may also harm the host cell. Strategy: target structures found only in the virus, such as viral protease, reverse transcriptase or polymerase, so the host cell is spared.
Rapid mutation and resistance. Viruses mutate quickly and new resistant strains appear, so a drug soon stops working. Strategy: use combination therapy (several drugs with different mechanisms at once, as in HIV treatment), keep developing new drugs, and prevent infection with vaccines.

iv3 marks

How does the secretion of hydrochloric acid influence the digestion?

Solution

Parietal cells secrete \ce{HCl}, which makes the stomach contents strongly acidic (pH 1.5 to 3.5). This helps digestion in several ways:

It converts inactive pepsinogen into active pepsin and gives the low pH at which pepsin works best, so protein digestion starts in the stomach.
It denatures food proteins, unfolding them so enzymes can reach their peptide bonds (a non-specific reaction).
It kills bacteria and other microbes in food, preventing infection.
The acidic food mixture entering the small intestine triggers the release of bicarbonate and bile for the next stage of digestion.

Too little acid gives poor protein digestion and infection; too much can cause heartburn and ulcers.

Long answer questionsp. 329

i7 marks

Discuss the link between the mechanism of action of opioids and the potential for drug addiction.

Solution

Mechanism of action of opioids

Opioids such as morphine, heroin and fentanyl have a shape similar to the body's own pain-relieving peptides, the endorphins. They bind to and activate **\mu (mu) opioid receptors** on nerve cells in the brain and spinal cord. In the pain pathway this closes \ce{Ca^2+} channels, so less pain transmitter is released, and opens \ce{K+} channels, so the next neuron fires less. Pain signals are blocked and the patient feels strong relief.

Effect on the reward pathway

Mu receptors are also present in the brain's reward centre. Normally, GABA neurons act as a brake on dopamine neurons there. Opioids inhibit these GABA neurons, so the brake is removed and a large amount of dopamine is released. Dopamine produces euphoria and a strong feeling of reward. The brain learns to link the drug with pleasure, so the user wants to repeat it.

\text{opioid}\rightarrow\mu\text{ receptor}\rightarrow\uparrow\text{dopamine}\rightarrow\text{euphoria}\rightarrow\text{repeated use}\rightarrow\text{tolerance, dependence}\rightarrow\text{addiction}

How repeated use becomes addiction

Tolerance: \mu receptors become desensitised and fewer of them remain on the cell surface, so a higher dose is needed for the same effect.
Physical dependence: the body adapts to the drug and makes fewer endorphins. When the drug is stopped, nerve cells become over-active and withdrawal symptoms appear: pain, sweating, diarrhoea, anxiety and sleeplessness.
Negative reinforcement: the user now takes the drug to avoid withdrawal, not only for pleasure.
Reset reward system: normal pleasures release too little dopamine to feel rewarding, so craving for the drug dominates. Compulsive use despite harm is addiction.

Conclusion

The same receptor action that gives pain relief also gives euphoria, so every drug that activates \mu receptors has addiction potential. Drugs that enter the brain faster (heroin and fentanyl are more fat-soluble) give a stronger 'rush' and are more addictive. Mu activation also slows breathing, so an overdose can kill. For these reasons opioids are prescription-only medicines, given at the lowest effective dose for the shortest time.

ii7 marks

Analyse the challenges involved in developing antiviral drugs.

Solution

Why viruses are hard to target

A virus is not a cell. It is genetic material (DNA or RNA) inside a protein coat, and it multiplies only inside a host cell, using the host's ribosomes and enzymes. An antiviral drug must therefore stop the virus inside our own cells without damaging them.

Main challenges

Replication inside host cells: the drug must enter the host cell and block the virus without interfering with host processes. Many compounds that stop viruses also poison host cells and cause toxic side effects.
Few drug targets: viruses have no cell wall, ribosomes or metabolic pathways, the targets of antibiotics. Only a few virus-specific proteins can be attacked, such as protease, reverse transcriptase, polymerase and the proteins used for entry and release.
Rapid mutation and resistance: RNA viruses such as HIV and influenza copy their genome with many errors and multiply very fast, so resistant strains appear quickly and a drug can become useless.
Viral diversity: each virus family has different enzymes, so a drug for HIV does not work against influenza. Broad-spectrum antivirals are very hard to design, and each new virus needs new research.
Dormancy and protective covering: herpes viruses and HIV can hide in cells in an inactive form. Drugs act only on multiplying viruses, so the infection is controlled but not cured.
Timing: symptoms appear after the virus has already multiplied, but antivirals work best when given early.
Testing and cost: many viruses are difficult to grow in the laboratory, and trials of safety and effectiveness are long and expensive.

How the challenges are being met

Designing drugs that target virus-only enzymes (protease and reverse transcriptase inhibitors).
Using drugs that are activated only inside infected cells; acyclovir is switched on by a viral enzyme, so healthy cells are spared.
Combination therapy to reduce resistance.
Boosting the host's immune response with interferons, and preventing infection with vaccines.

Conclusion

The central problem is selectivity: stopping a parasite that lives inside our own cells. Progress has turned HIV and hepatitis C from fatal or chronic diseases into treatable ones, but rapid mutation means new antiviral drugs will always be needed.

iii7 marks

Explain the relationship between the Minimum Effective Concentration (MEC) and the Maximum Tolerated Concentration (MTC). How do these parameters define the therapeutic window?

Solution

Definitions

MEC: The lowest concentration of a drug in the bloodstream that triggers the desired therapeutic effect. Below it the drug may not be effective.
MTC: The highest concentration of a drug in the bloodstream that a patient can bear without severe side effects or toxicity. Above it the drug is toxic.

Relationship between MEC and MTC

For a useful drug the MTC is always higher than the MEC. The gap between them is the safety margin of the drug.
A wide gap (MTC much larger than MEC, as for penicillin) means the drug is safe and easy to dose.
A narrow gap (as for digoxin, lithium or warfarin) means a small overdose can be toxic, so blood levels must be monitored.
The ratio of toxic to effective levels is the idea behind the therapeutic index, TI=TD_{50}/ED_{50}.

How they define the therapeutic window

The therapeutic window is the concentration range between the MEC (lower boundary) and the MTC (upper boundary). Inside it the drug is both effective and safe. Below the MEC the treatment is inadequate; above the MTC the patient suffers toxicity.

\text{MEC}\le C_{\text{blood}}\le\text{MTC}

Drug level in the blood after one dose

The therapeutic window is the band between the MEC and the MTC. A normal dose stays inside it; a double dose crosses the MTC and becomes toxic.

After a dose the blood level rises, passes the MEC (the drug starts to work), reaches a peak and then falls as the drug is metabolised and excreted. When it drops below the MEC the effect ends, so the next dose must be given. The dose size keeps the peak below the MTC, and the time between doses keeps the level above the MEC.

Factors that shift the window

Individual variability (genes, age, health), drug interactions and patient characteristics (weight, liver or kidney disease) change how fast the drug is absorbed and removed, so the dose may have to be adjusted to keep the concentration inside the window.

iv8 marks

Describe the chemical structure of aspirin and penicillin, highlighting the functional groups that are critical for their mechanisms of action. Explain how these structures relate to their respective therapeutic uses.

Solution

Aspirin: structure

Aspirin is acetylsalicylic acid, \ce{C9H8O4}. It has a benzene ring, a carboxylic acid group (\ce{-COOH}) and, on the neighbouring carbon, an ester (acetoxy) group (\ce{-OCOCH3}).

aspirin benzene ring, \ce{-COOH} and acetoxy ester group

Aspirin: groups critical for its action

Ester (acetyl) group: aspirin acts as an acetylating agent. It transfers its acetyl group to a serine \ce{-OH} in the active site of cyclooxygenase (COX), blocking the enzyme permanently. Salicylic acid, which lacks this group, is only a weak, reversible inhibitor.
Carboxylic acid group: as \ce{-COO-} it is attracted to a positive group in the enzyme's channel and holds the molecule in the right position.
Benzene ring: the flat ring fits the narrow, non-polar channel of the enzyme.

Aspirin: link to uses

With COX blocked, fewer prostaglandins are made, so aspirin is an analgesic, anti-inflammatory and antipyretic. Less thromboxane is made, so platelets clump less; low-dose aspirin prevents heart attacks and strokes. The acidic \ce{-COOH} group also explains its side effect of stomach irritation.

Penicillin: structure

Penicillin has a **four-membered \beta-lactam ring (a cyclic amide) fused to a five-membered thiazolidine ring (containing S and N), a carboxylic acid group, two methyl groups and an amide side chain** \ce{R-CO-NH-}.

penicillin G \beta-lactam fused to thiazolidine; R = benzyl

Penicillin: groups critical for its action

**\beta-lactam ring:** its bond angles are about 90^\circ, so the ring is strained and reactive. It opens and bonds covalently to a serine in the bacterial enzyme transpeptidase, which can then no longer cross-link the cell wall.
Thiazolidine ring: keeps the \beta-lactam ring bent and strained, and gives the molecule a shape like the peptide end (D-Ala-D-Ala) that the enzyme normally binds.
Carboxylic acid group: binds to the enzyme's active site and allows water-soluble salts for injection.
Side chain R: decides acid stability, the range of bacteria killed and resistance to \beta-lactamase.

Penicillin: link to uses

Only bacteria have peptidoglycan cell walls, so penicillin kills them without harming human cells. It is therefore a safe antibacterial drug for pneumonia, meningitis, skin and throat infections and syphilis, especially those caused by Gram-positive bacteria. It is useless against viruses and fungi, which have no such wall.

v8 marks

A patient presents with symptoms of a bacterial infection. The doctor prescribes penicillin. Explain how penicillin works to treat the infection. Discuss potential resistance mechanisms that bacteria might employ against penicillin and how these mechanisms can be overcome.

Solution

How penicillin treats the infection

The bacterial cell wall is made of peptidoglycan chains that the enzyme transpeptidase cross-links.
Penicillin resembles the peptide end that the enzyme joins, so it enters the active site.
Its strained **\beta-lactam ring** opens and bonds covalently to the enzyme, blocking it permanently.
Growing bacteria build weak walls; water enters by osmosis, the cells burst and die. The immune system clears the rest.

Human cells have no cell wall, so the drug is selectively toxic to bacteria.

Resistance mechanisms

**\beta-lactamase (penicillinase):** the bacterium makes an enzyme that hydrolyses the \beta-lactam ring and turns penicillin into inactive penicilloic acid before it reaches its target (for example Staphylococcus aureus).
Altered target: the bacterium makes a changed transpeptidase (penicillin-binding protein) that penicillin cannot bind well, as in MRSA.
Reduced entry: Gram-negative bacteria reduce the pores in their outer membrane, so less drug gets in.
Efflux pumps: membrane proteins pump the drug out of the cell.
Spread of resistance genes: resistance genes on plasmids pass from one bacterium to another, so resistance spreads quickly.

How resistance can be overcome

Give a **\beta-lactamase inhibitor** with the penicillin, such as clavulanic acid with amoxicillin (co-amoxiclav). The inhibitor protects the \beta-lactam ring.
Use **\beta-lactamase-resistant penicillins** such as methicillin or flucloxacillin, whose bulky side chain shields the ring.
Switch to other antibiotics (cephalosporins, carbapenems, or vancomycin for MRSA) chosen after a culture and sensitivity test.
Responsible use: antibiotics only on prescription, the correct dose, completing the full course, and no antibiotics for viral infections or for growth promotion in animals.
Infection control in hospitals (hand washing, isolation) and research into new antibiotics.

vi7 marks

Identify and describe the main types of opioid receptors in the brain. Discuss their roles in pain modulation and the physiological effects of their activation by opiates.

Solution

Opioid receptors

Opioid receptors are protein molecules on nerve cells in the brain, spinal cord and gut. They are part of the body's natural pain-control system and are normally activated by the body's own peptides: endorphins, enkephalins and dynorphins. Opiates such as morphine activate the same receptors.

Receptor	Main natural activator	Effects of activation
Mu (\mu)	endorphins	strong analgesia (main target of clinical opioids), euphoria, respiratory depression, sedation, constipation, pinpoint pupils, physical dependence
Delta (\delta)	enkephalins	function not fully understood; adds to pain relief and helps regulate mood
Kappa (\kappa)	dynorphins	pain relief (mainly in the spinal cord), sedation, and in some cases dysphoria and hallucinations

Role in pain modulation

Spinal cord: activated receptors close \ce{Ca^2+} channels in the pain nerve ending, so less pain transmitter (substance P, glutamate) is released, and open \ce{K+} channels in the next neuron, so it fires less. The pain signal is weakened before it reaches the brain.
Brainstem: receptors switch on nerve pathways that run down to the spinal cord and block incoming pain signals.
Higher brain (limbic system): receptors change the emotional response to pain, so the pain is still felt but is less distressing.

Physiological effects of activation by opiates

Analgesia: relief of moderate to severe pain (mainly \mu).
Euphoria: dopamine release in the reward centre (\mu); the basis of abuse.
Respiratory depression: slowed breathing through \mu receptors in the brainstem; the usual cause of death in overdose.
Cough suppression and constipation: reduced cough reflex and slower bowel movement, used medically for cough and diarrhoea.
Dysphoria and hallucinations: possible with \kappa activation.
Tolerance and dependence with long-term use.

Conclusion

The \mu receptor is both the most useful (pain relief) and the most dangerous (euphoria, addiction and breathing depression). Research on drugs that act more on \kappa or \delta receptors aims to give pain relief with less risk of addiction.

vii8 marks

Analyse the impact of long-term opiate use on brain chemistry and function. Discuss the changes in receptor density and neurotransmitter levels that occur with prolonged exposure to opiates. Evaluate the implications of these changes for treatment options and recovery strategies for opiate addiction.

Solution

Impact on brain chemistry and function

The brain always tries to keep its chemistry balanced. When opiates are present all the time, nerve cells adapt to them. These adaptations cause tolerance, physical dependence and addiction, and they reverse only slowly after the drug is stopped.

Changes in receptor density

Desensitisation: \mu receptors that are activated constantly become chemically 'switched off' and respond less.
Down-regulation: many receptors are taken inside the cell, so the receptor density on the cell surface falls. Higher doses are needed for the same effect (tolerance).
Fewer dopamine receptors: brain scans of addicted people show fewer dopamine receptors in the reward circuit, so normal rewards feel weak.

Changes in neurotransmitter levels

Dopamine: each dose gives a large surge, but the normal (baseline) level and response fall, causing low mood and strong craving.
Endorphins: natural production falls because the drug is doing their job.
Noradrenaline: nerve cells slowed by the drug adapt by becoming more excitable. When the drug is removed, a noradrenaline surge causes withdrawal: anxiety, sweating, fast heartbeat and diarrhoea.
Glutamate (learning circuits): the brain links people, places and objects with the drug, so these cues trigger craving and relapse.

Implications for treatment options

Supervised detoxification: gradual reduction of the dose, with medicines (such as clonidine) that calm the noradrenaline surge.
Methadone: a long-acting \mu agonist taken once a day by mouth. It occupies the receptors, prevents withdrawal and craving, and gives little 'high'.
Buprenorphine: a partial \mu agonist; it has a ceiling on breathing depression, so it is safer.
Naltrexone: a \mu antagonist that blocks the euphoria and helps prevent relapse after detoxification.
Naloxone: an antagonist used in emergencies to reverse an overdose.

Recovery strategies

Because the brain changes last for months, medicines work best together with counselling, cognitive behavioural therapy, support groups, family support and long-term follow-up. Patients learn to avoid triggers and cope with craving. After a period without the drug, tolerance falls, so a relapse at the old dose can cause a fatal overdose; patients must be warned about this.

Evaluation

Addiction is a long-term brain disorder, not only a lack of willpower. Treatment that combines medication with psychological and social support gives the best recovery rates.

Exam focus

Define the therapeutic window. Explain MEC and MTC with a labelled sketch. (long)
The first SLO of the unit; a common short question and a good Section C question with a graph.
Go to answer
Mechanism of action, uses and structure of aspirin. (short)
Aspirin appears in two SLOs; COX inhibition and the ester group are favourite short questions.
Go to answer
How does penicillin kill bacteria? Name its key structural feature. (short)
Transpeptidase inhibition by the \beta-lactam ring is the core idea of the penicillin topic.
Go to answer
Describe the structures of aspirin and penicillin and relate their functional groups to their action and uses. (long)
Combines two SLOs in one comprehensive question.
Go to answer
Types of opioid receptors and the effects of their activation. (long)
Know the \mu, \delta, \kappa table; \mu is the analgesic receptor (book exercise MCQ ii).
Go to answer
Link between the mechanism of opioids and addiction. (long)
Dopamine release, tolerance and dependence; book long question i and MCQ xi.
Go to answer
Role of hydrochloric acid in the stomach and in activating pepsin. (short)
Two of the four book short questions are on stomach acid.
Go to answer
What are non-specific reactions and active metabolites? Give an example of each. (short)
A named SLO that needs crisp definitions and examples.
Go to answer
Challenges in treating viral infections and strategies to overcome them. (long)
Book short iii and long ii; pair each challenge with a strategy.
Go to answer
How penicillin resistance arises and how it can be overcome. (long)
Scenario-type comprehensive question (book long v).
Go to answer